DESCRIPTION(Adapted from applicant?s abstract): The neurobiology underlying schizophrenia, a devastating psychiatric disorder affecting 1 percent of the population, is not yet fully understood. It has been theorized that patients with schizophrenia suffer from a sensorimotor gating deficit, which has been measured behaviorally through disruptions of prepulse inhibition of the starde response (PPI). PPI, a multimodal phenomenon present across species, is also disrupted by PCP (phencyclidine), a psychotomimetic drug which acts as an NMDA antagonist. NMDA receptors have been shown to work in conjunction with the more recently discovered metabotropic glutamate receptors (mGluRs). The goal of this project is to use recently developed knockout mice (which lack the gene responsible for the expression of a particular mGluR) to investigate the role of the mGluRs, specifically mGluR5, in the modulation of PPI and locomotor behavior. As mouse strains vary widely in teir responses to pharmacological manipulations, each background strain will need to be characterized separately. Additionally, the compounds affecting the mGluRs have only been developed extremely recently. A number of background pharmacology studies using both classic and novel ligands therefore will be conducted. In summary, this application seeks to determine the role of the metabotropic glutamate receptors, specifically mGluR5, in the modulation of PPI and locomotor behavior through the use of genetically altered mice and newly available pharmacological agents.